Prefrontal cortical GABA modulation of spatial reference and working memory

Abstract

Background: Dysfunction in prefrontal cortex (PFC) GABA transmission has been proposed to contribute to cognitive dysfunction in schizophrenia, yet how this system regulates different cognitive and mnemonic functions remains unclear.

Methods: We assessed the effects of pharmacological reduction of GABAA signaling in the medial PFC of rats on spatial reference/working memory using different versions of the radial-arm maze task. We used a massed-trials procedure to probe how PFC GABA regulates susceptibility to proactive interference. Male rats were well-trained to retrieve food from the same 4 arms of an 8-arm maze, receiving 5 trials/day (1-2 min intervals).

Results: Infusions of the GABAA receptor antagonist bicuculline (12.5-50 ng) markedly increased working and reference memory errors and response latencies. Similar treatments also impaired short-term memory on an 8-baited arm task. These effects did not appear to be due to increased susceptibility to proactive interference. In contrast, PFC inactivation via infusion of GABA agonists baclofen/muscimol did not affect reference/working memory. In comparison to the pronounced effects on the 8-arm maze tasks, PFC GABAA antagonism only causes a slight and transient decrease in accuracy on a 2-arm spatial discrimination.

Conclusions: These findings demonstrate that prefrontal GABA hypofunction severely disrupts spatial reference and short-term memory and that disinhibition of the PFC can, in some instances, perturb memory processes not normally dependent on the frontal lobes. Moreover, these impairments closely resemble those observed in schizophrenic patients, suggesting that perturbation in PFC GABA signaling may contribute to these types of cognitive deficits associated with the disorder.

Keywords: GABA; prefrontal cortex; reference memory; schizophrenia; working memory..

Figure 1.

Location of all acceptable infusion placements within the medial PFC. Different symbols denote the locations of infusions for rats for each of the four specific experiments.

Figure 2.

Prefrontal GABA_A antagonism blockade disrupts spatial reference and working memory performance on a radial maze task. For this and all other figures, values displayed are the mean +/- SEM. (A) Infusion of both a 50 and 12.5ng dose of bicuculline increased the number of errors on Trial 1, while only the 50ng dose increased the average number of errors on Trials 2–5. (B) Both doses of bicuculline increased the total number of reference and working memory committed over the 5 trials of a test session. However, the 50ng dose caused significantly more reference memory errors than the 12.5ng dose. (C) Intra-PFC infusions of 50ng bicuculline increased the time to initiate a trial, specifically in Trials 1 and 2. (D) The 50ng dose increased the average time per subsequent choice across all trials. *p < 0.05 vs saline, +p < 0.05 50ng vs 12.5ng.

Figure 3.

Prefrontal GABA_A receptor antagonism disrupts short-term memory on an 8-arm foraging task. (A) Intra-PFC infusion of 50ng bicuculline increased the total number of errors committed across the 5 trials of a test session. (B) These treatments the number of errors made during for Trial 1 and subsequent errors during Trials 2–5. Under control conditions, rats made significantly more errors during Trials 2–5 relative to the first trial, indicative of an increase proactive interference during the latter trials. (C) Infusion of bicuculline increased the time to initiate during the first trial of a test session. (D) These treatments increased the average time per subsequent choice during Trials 1–3. *p < 0.05 vs saline, +p < 0.05 Trials 1 vs 2–5 for saline condition.

Figure 4.

PFC inactivation does not affect spatial reference/working memory performance. (A) Inactivation of the medial PFC with infusion of the GABA agonists baclofen and muscimol had no effect on the number of errors on Trial 1 or the average number of errors on Trials 2–5. (B) PFC inactivation did not alter on the total number of reference or working memory errors relative to saline. (C) Inactivaiton of the PFC increased the latency to initiate a trial during the first trial of a test session, but did not affect the average time per subsequent choice (D). *p < 0.05 vs saline.

Figure 5.

Prefrontal GABA_A receptor antagonism and performance of a 2-arm spatial discrimination. (A) Intra-PFC infusion of 50ng bicuculline did not alter the total number of errors committed across the 20 trials of a spatial discrimination test session. (B) These treatments did cause a slight increase in errors made during the first 4 trials, but this effect disappear during the latter trials of a test session. (c) Choice latencies were also increased during the first 4 trials. *p < 0.05 vs saline.